WO2005075488A1 - Procede de fabrication de fosphenytoine, sel de sodium - Google Patents
Procede de fabrication de fosphenytoine, sel de sodium Download PDFInfo
- Publication number
- WO2005075488A1 WO2005075488A1 PCT/CH2004/000063 CH2004000063W WO2005075488A1 WO 2005075488 A1 WO2005075488 A1 WO 2005075488A1 CH 2004000063 W CH2004000063 W CH 2004000063W WO 2005075488 A1 WO2005075488 A1 WO 2005075488A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- diphenyl
- phosphite
- methyl
- ester
- phosphonooxy
- Prior art date
Links
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 title claims abstract description 17
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title abstract description 7
- 229960000693 fosphenytoin Drugs 0.000 title abstract description 7
- 239000011734 sodium Substances 0.000 title abstract description 7
- 229910052708 sodium Inorganic materials 0.000 title abstract description 7
- 238000004519 manufacturing process Methods 0.000 title abstract description 3
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims abstract description 16
- QQBKLRXLVRDKEB-UHFFFAOYSA-N 3-(hydroxymethyl)-5,5-diphenylimidazolidine-2,4-dione Chemical compound O=C1N(CO)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 QQBKLRXLVRDKEB-UHFFFAOYSA-N 0.000 claims abstract description 15
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004185 ester group Chemical group 0.000 claims abstract description 12
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims abstract description 10
- RQKYHDHLEMEVDR-UHFFFAOYSA-N oxo-bis(phenylmethoxy)phosphanium Chemical compound C=1C=CC=CC=1CO[P+](=O)OCC1=CC=CC=C1 RQKYHDHLEMEVDR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims abstract description 9
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 150000005690 diesters Chemical class 0.000 claims abstract description 6
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 5
- 150000005691 triesters Chemical class 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- 150000002148 esters Chemical class 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 11
- 230000004913 activation Effects 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- GBZICLAYYKRVGI-UHFFFAOYSA-N dibenzyl (2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl phosphate Chemical compound O=C1NC(C=2C=CC=CC=2)(C=2C=CC=CC=2)C(=O)N1COP(=O)(OCC=1C=CC=CC=1)OCC1=CC=CC=C1 GBZICLAYYKRVGI-UHFFFAOYSA-N 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 5
- GQPXYJNXTAFDLT-UHFFFAOYSA-L disodium;(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl phosphate Chemical compound [Na+].[Na+].O=C1N(COP([O-])(=O)[O-])C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 GQPXYJNXTAFDLT-UHFFFAOYSA-L 0.000 claims description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 4
- 230000002140 halogenating effect Effects 0.000 claims description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- KJWHEZXBZQXVSA-UHFFFAOYSA-N tris(prop-2-enyl) phosphite Chemical group C=CCOP(OCC=C)OCC=C KJWHEZXBZQXVSA-UHFFFAOYSA-N 0.000 claims description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 2
- NAMIALUNKOUUCM-UHFFFAOYSA-N COC1=CC(OC)=CC=C1COP(O)OCC1=CC=C(OC)C=C1OC Chemical compound COC1=CC(OC)=CC=C1COP(O)OCC1=CC=C(OC)C=C1OC NAMIALUNKOUUCM-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- WIVUOZUCIBDPAX-UHFFFAOYSA-N bis(2-trimethylsilylethyl) hydrogen phosphite Chemical compound C[Si](C)(C)CCOP(O)OCC[Si](C)(C)C WIVUOZUCIBDPAX-UHFFFAOYSA-N 0.000 claims description 2
- XNNQFQFUQLJSQT-UHFFFAOYSA-N bromo(trichloro)methane Chemical compound ClC(Cl)(Cl)Br XNNQFQFUQLJSQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims description 2
- CZHYKKAKFWLGJO-UHFFFAOYSA-N dimethyl phosphite Chemical compound COP([O-])OC CZHYKKAKFWLGJO-UHFFFAOYSA-N 0.000 claims description 2
- 239000007974 sodium acetate buffer Substances 0.000 claims description 2
- 229950009390 symclosene Drugs 0.000 claims description 2
- KKFOMYPMTJLQGA-UHFFFAOYSA-N tribenzyl phosphite Chemical compound C=1C=CC=CC=1COP(OCC=1C=CC=CC=1)OCC1=CC=CC=C1 KKFOMYPMTJLQGA-UHFFFAOYSA-N 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- UKOLAOBLGCLVKH-UHFFFAOYSA-N P(OC(C)(C)C)(OC(C)(C)C)O.P(O)(O)O Chemical compound P(OC(C)(C)C)(OC(C)(C)C)O.P(O)(O)O UKOLAOBLGCLVKH-UHFFFAOYSA-N 0.000 claims 1
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 4
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 2
- 230000003556 anti-epileptic effect Effects 0.000 abstract description 2
- 239000003416 antiarrhythmic agent Substances 0.000 abstract description 2
- 229960003965 antiepileptics Drugs 0.000 abstract description 2
- 230000026030 halogenation Effects 0.000 abstract description 2
- 238000005658 halogenation reaction Methods 0.000 abstract description 2
- CKBXTXIAQHEVAB-UHFFFAOYSA-N (2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl dihydrogen phosphate;sodium Chemical compound [Na].[Na].O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 CKBXTXIAQHEVAB-UHFFFAOYSA-N 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 8
- 239000012071 phase Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- -1 alkali metal phosphonate Chemical class 0.000 description 4
- 229960002036 phenytoin Drugs 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical group C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000004042 decolorization Methods 0.000 description 3
- 239000010502 orange oil Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- CPAOLXXQYDLLFS-UHFFFAOYSA-N (2,4-dioxoimidazolidin-1-yl)methyl dihydrogen phosphate Chemical compound P(=O)(O)(O)OCN1C(NC(C1)=O)=O CPAOLXXQYDLLFS-UHFFFAOYSA-N 0.000 description 1
- PYDRZMYWNKZPBY-UHFFFAOYSA-N (2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl diethyl phosphate Chemical compound O=C1N(COP(=O)(OCC)OCC)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 PYDRZMYWNKZPBY-UHFFFAOYSA-N 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-Me3C6H3 Natural products CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 125000002927 2-methoxybenzyl group Chemical group [H]C1=C([H])C([H])=C(C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- MSZRXMLCSVUNIJ-UHFFFAOYSA-N [Ag].C=1C=CC=CC=1COP(=O)OCC1=CC=CC=C1 Chemical compound [Ag].C=1C=CC=CC=1COP(=O)OCC1=CC=CC=C1 MSZRXMLCSVUNIJ-UHFFFAOYSA-N 0.000 description 1
- MGFIZMMCIAGQGB-UHFFFAOYSA-N [Na].C=1C=CC=CC=1COP(=O)OCC1=CC=CC=C1 Chemical compound [Na].C=1C=CC=CC=1COP(=O)OCC1=CC=CC=C1 MGFIZMMCIAGQGB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229940029783 cerebyx Drugs 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DYUGVWSETOTNKQ-UHFFFAOYSA-N dibenzyl hydrogen phosphite Chemical class C=1C=CC=CC=1COP(O)OCC1=CC=CC=C1 DYUGVWSETOTNKQ-UHFFFAOYSA-N 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- RRJHOMPUEYYASJ-UHFFFAOYSA-N ditert-butyl hydrogen phosphite Chemical compound CC(C)(C)OP(O)OC(C)(C)C RRJHOMPUEYYASJ-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229940082150 encore Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 125000006502 nitrobenzyl group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000008301 phosphite esters Chemical class 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- RPACBEVZENYWOL-XFULWGLBSA-M sodium;(2r)-2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate Chemical compound [Na+].C=1C=C(Cl)C=CC=1OCCCCCC[C@]1(C(=O)[O-])CO1 RPACBEVZENYWOL-XFULWGLBSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- Sodium fosphenytoin is the short name for the 5,5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione disodium salt, which is used as an anticonvulsant, antiepileptic and antiarrhythmic agent.
- Preparations containing sodium fosphenytoin are sold under the name Cerebyx.
- sodium fosphenytoin is prepared by adding hydroxymethylphenytoin, i.e. 3- (hydroxymethyl) -5, 5-diphenyl-2, 4-imidazolinedione, converted into 3-chloromethyl-phenytoin, reacted with silver dibenzylphosphonate, cleaved the two benzyl groups in the diester obtained by catalytic hydrogenation and finally using sodium hydroxide solution the desired di -Sodium salt forms.
- diesters of the type mentioned can be prepared without the need to use a silver salt by reacting 3-chloro- or bromomethyl-phenytoin with an alkali metal phosphonate, such as potassium or sodium dibenzyl phosphonate.
- an alkali metal phosphonate such as potassium or sodium dibenzyl phosphonate.
- sodium phosphenytoin can be prepared advantageously by adding 3- (hydroxymethyl) -5, 5-diphenyl-2, 4-imidazolinedione with a di- or triester of phosphorous acid activated by an oxidizing agent, the ester groups of which can be split off selectively from the reaction product, reacted, split off the ester groups from the phosphoric acid diester-2, 5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl ester obtained and the 5, 5-diphenyl-3- obtained [(phosphonooxy) methyl] -2, 4-imidazolidinedione converted into its disodium salt.
- a halogenating agent such as elemental bromine, N-bromosuccinimide, 1, 3-dibromo-5, 5-dimethylhydantoin, tetrabromomethane, trichlorobromomethane, elemental chlorine, N-chlorosuccinimide, trichloroisocyanuric acid and hexachloroacetone acid, is expediently used as the oxidizing agent for activating the phosphorous acid ester the like, with elemental bromine being preferred.
- Such halogenation is conveniently carried out in the presence of a base, for example in the presence of pyridine, 2,6-lutidine, 2, 4, 6-collidine, triethylamine and the like.
- a polar aprotic solvent such as dichloromethane, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, 1-methyl-2-pyrrolione, 1, 3-dimethyl-2-imidazolidinone and the like, is expediently used as the solvent.
- phosphite esters 0.5-5.0 equivalents, preferably 1.1-1.4 equivalents, of phosphite esters, 0.5-10.0 equivalents, preferably 1.5-3.0 equivalents of oxidizing agents and 0.5-10.0 equivalents, preferably 1.5-3.0 equivalents of base, based on the hydroxymethylphenytoin.
- ester groups which can be cleaved selectively from the reaction product are, in particular, those whose cleavage under mild acidic conditions (e.g. tert-butyl or 2,2,2-trichloroethyl) is oxidative (e.g. silylated
- Alkyl groups can be removed under mild basic conditions (e.g. ethyl) or photochemically (e.g. nitrobenzyl), but especially hydrogenolytically removable groups such as the benzyl group and substituted benzyl groups such as 4-methoxybenzyl, 4-bromobenzyl, 2-methoxybenzyl, 2,4 -
- esters of phosphorous acid their ester groups are selective from the reaction product can be split off, in particular di-tert-butyl phosphite, dibenzyl phosphite, bis-4-methoxybenzyl phosphite, bis-4-bromobenzyl phosphite, bis-4-nitrobenzyl phosphite, bis- (2,4-dimethoxybenzyl) phosphite, bis-2 , 2, 2-trichloroethyl phosphite, bis (2-trimethylsilylethyl) phosphite, triallyl phosphite or tribenzyl phosphite and also dimethyl phosphite, diethyl phosphite, trimethyl phosphite or triethyl phosphite.
- esters of phosphorous acid used in the process according to the invention are known or easily accessible by any process familiar to a person skilled in the art.
- the cleavage of the ester groups from the 2, 5-dioxo-4, 4-diphenylimidazolidin-1-ylmethyl ester of phosphoric acid, in particular by hydrogenation, is conveniently carried out in a mixture of water and a water-miscible solvent, for example in methanol / water , Isopropanol / water, acetone / water, 2-butanone / water and the like; preferably a buffer is added, for example acetic acid / acetate.
- 3- (hydroxymethyl) -5, 5-diphenyl-2,4-imidazolinedione is replaced by elemental bromine or N-
- the activation of the dibenzyl phosphite by means of elemental bromine or N-bromosuccinimide and the reaction of the activation product with the 3- (hydroxymethyl) -5, 5-diphenyl -2, 4 -imidazolinedione and on the other hand the hydrogenation of the phosphoric acid dibenzyl ester-2, 5-dioxo-4, 4-diphenyl-imidazolidin-1-ylmethyl ester and the conversion of the 5,5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione into its disodium salt in carried out one work step each.
- the temperature for the various operations of the method according to the invention is expediently in the range from approximately -30 ° C. to approximately + 80 ° C., preferably in the range from approximately -10 ° C. to approximately + 30 ° C.
- the process according to the invention does not use a phosphate (phosphorus in the + V oxidation state), but rather a phosphite (phosphorus in the + III oxidation state).
- This phosphite is activated in situ with an oxidizing agent, preferably a halogenating agent, and then reacted directly with the hydroxymethylphenytoin known from the literature and readily available from commercially available phenytoin.
- a phosphoric acid diesester-2 is prepared in a single operation in order to prepare 5, 5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione disodium salt , 5-dioxo-4, 4-diphenyl-imidazolidin-l-ylmethyl ester, whose phosphoric diester structural element can be cleaved selectively, in 5, 5-diphenyl-3- [(phosphonooxy) methyl] -2, 4-imidazolidinedione and this in transferred its disodium salt; this aspect is an essential part of the present invention, also taken on its own.
- the orange suspension obtained was mixed with 250 g of water and 50 g of 36% sodium thiosulfate solution (about 2 mmol / g), whereupon discoloration was observed rapidly. After adding 650 ml of ethyl acetate, the phases were separated and the organic phase was washed with 50 g of saturated sodium carbonate solution. The organic phase was concentrated and the yellow-orange oil obtained was taken up in a mixture of 350 ml of acetonitrile and 350 ml of water. After inoculation, a voluminous precipitate precipitated out, which was filtered off and dried in vacuo; Yield 200 g (68%).
- the orange suspension obtained was mixed with 20 g of water and 1 g of 36% sodium thiosulfate solution, whereupon decolorization was observed rapidly. After adding 50 ml of ethyl acetate, the phases were separated and the organic phase was saturated twice with 20 ml each
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Abstract
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PCT/CH2004/000063 WO2005075488A1 (fr) | 2004-02-05 | 2004-02-05 | Procede de fabrication de fosphenytoine, sel de sodium |
US10/587,189 US20070219378A1 (en) | 2004-02-05 | 2004-02-05 | Method for Producing Sodium Fosphenytoin |
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PCT/CH2004/000063 WO2005075488A1 (fr) | 2004-02-05 | 2004-02-05 | Procede de fabrication de fosphenytoine, sel de sodium |
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WO2007014326A1 (fr) * | 2005-07-27 | 2007-02-01 | University Of Southern California | Acides amines a base de coumarine pouvant etre utilises dans des analyses d'activite enzymatique et de specificite de substrat |
WO2007022568A1 (fr) * | 2005-08-25 | 2007-03-01 | Steven Michael Weiss | Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne |
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CN106279279B (zh) * | 2016-08-15 | 2018-06-01 | 广安凯特制药有限公司 | 一种磷苯妥英钠的制备工艺 |
Citations (1)
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WO1997041132A1 (fr) * | 1996-04-30 | 1997-11-06 | Warner-Lambert Company | Procede perfectionne pour la synthese de diesters de l'ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylique de l'acide phosphorique |
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CH696765A5 (de) * | 2004-06-02 | 2007-11-30 | Cilag Ltd | Verfahren zur Herstellung von Natrium-fosphenytoin. |
-
2004
- 2004-02-05 US US10/587,189 patent/US20070219378A1/en not_active Abandoned
- 2004-02-05 WO PCT/CH2004/000063 patent/WO2005075488A1/fr active Application Filing
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WO1997041132A1 (fr) * | 1996-04-30 | 1997-11-06 | Warner-Lambert Company | Procede perfectionne pour la synthese de diesters de l'ester 2,5-dioxo-4,4-diphenyl-imidazolidin-1-ylmethylique de l'acide phosphorique |
Non-Patent Citations (2)
Title |
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OZA V B ET AL: "A MILD PREPARATION OF PROTECTED PHOSPHATE ESTERS FROM ALCOHOLS", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 60, no. 12, 16 June 1995 (1995-06-16), pages 3680 - 3684, XP000509383, ISSN: 0022-3263 * |
VARIA S A ET AL: "PHENYTOIN PRODRUGS III: WATER-SOLUBLE PRODRUGS FOR ORAL AND/OR PARENTERAL USE", JOURNAL OF PHARMACEUTICAL SCIENCES, AMERICAN PHARMACEUTICAL ASSOCIATION. WASHINGTON, US, vol. 73, no. 8, 1 August 1984 (1984-08-01), pages 1068 - 1073, XP000604620, ISSN: 0022-3549 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007014326A1 (fr) * | 2005-07-27 | 2007-02-01 | University Of Southern California | Acides amines a base de coumarine pouvant etre utilises dans des analyses d'activite enzymatique et de specificite de substrat |
US9045507B2 (en) | 2005-07-27 | 2015-06-02 | University Of Southern California | Coumarin-based amino acids for use in enzyme activity and substrate specificity assays |
WO2007022568A1 (fr) * | 2005-08-25 | 2007-03-01 | Steven Michael Weiss | Réduction d’un dommage myocardique et de l’incidence d’une arythmie survenant à la suite d’une perte, d’une réduction ou d’une interruption de la circulation coronarienne |
US9629817B2 (en) | 2005-08-25 | 2017-04-25 | Steven Michael Weiss | Reducing myocardial damage and the incidence of arrhythmia arising from loss, reduction or interruption in coronary blood flow |
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